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Tamoxifen is widely used for the treatment of hormonally responsive breast cancers. However, some resistant breast cancers develop a growth proliferative response to this drug, as evidenced by tumor regression upon its withdrawal. To elucidate the molecular mediators of this paradox, tissue samples from a patient with tamoxifen-stimulated breast cancer were analyzed. These studies revealed that loss of the cyclin-dependent kinase inhibitor p21 was associated with a tamoxifen growth-inducing phenotype. Immortalized human breast epithelial cells with somatic deletion of the p21 gene were then generated and displayed a growth proliferative response to tamoxifen, whereas p21 wild-type cells demonstrated growth inhibition upon tamoxifen exposure. Mutational and biochemical analyses revealed that loss of p21's cyclindependent kinase inhibitory property results in hyperphosphorylation of estrogen receptor-␣, with subsequent increased gene expression of estrogen receptor-regulated genes. These data reveal a previously uncharacterized molecular mechanism of tamoxifen resistance and have potential clinical implications for the management of tamoxifen-resistant breast cancers.estrogen receptor ͉ p21 knockout ͉ drug resistance ͉ selective estrogen receptor modulator

Objective The development of venothromboembolisms (VTEs), including deep vein thrombosis (DVT) and pulmonary emboli (PE), is common in brain tumor patients. Their development can be catastrophic. Studies evaluating pre-operative clinical factors that predispose patients to the development of VTE are few and limited. An understanding may help risk stratify patients and guide subsequent therapy aimed at reducing the risk of DVTs/PEs. Methods All adult patients who underwent surgery for an intracranial tumor at an academic tertiary care institution between 1998 and 2008 were retrospectively reviewed. Stepwise multivariate logistical regression analysis was used to identify pre-operative factors associated with the development of peri-operative (within 30 days of surgery) DVTs/PEs among patients who underwent surgery of their intracranial tumor. Results Of the 4293 patients in this study, 126 (3%) patients developed DVT and/or PE in the peri-operative period. The pre-operative factors independently associated with the development of DVTs/PEs were: poorer Karnofsky performance scale (KPS) [odds ratio (OR), 1.040; 95% confidence interval (CI), 1.026–1.052; P<0.0001], high grade glioma (OR, 1.702; 95% CI, 1.176–2.465; P=0.005), older age (OR, 1.033; 95% CI, 1.020–1.046; P<0.0001), hypertension (OR, 1.785; 95% CI, 1.180–2.699; P=0.006), and motor deficit (OR, 1.854; 95% CI, 1.244–2.763; P=0.002). Eighty six per cent of the patients with DVTs/PEs were treated with either unfractionated or low molecular weight heparin, and 4% of these patients developed intracranial hemorrhage. Discussion The present study found that poorer functional status, older age, pre-operative motor deficit, high grade glioma, and hypertension each independently increased the risk of developing peri-operative DVTs/PEs. These findings may provide patients and physicians with prognostic information that may guide therapies aimed at minimizing the development of peri-operative DVTs/PEs.

IntroductionGlioblastoma is the most common primary malignant brain tumor, and is refractory to surgical resection, radiation, and chemotherapy. Human mesenchymal stem cells (hMSC) may be harvested from bone marrow (BMSC) and adipose (AMSC) tissue. These cells are a promising avenue of investigation for the delivery of adjuvant therapies. Despite extensive research into putative mechanisms for the tumor tropism of MSCs, there remains no direct comparison of the efficacy and specificity of AMSC and BMSC tropism towards glioma.MethodsUnder an IRB-approved protocol, intraoperative human Adipose MSCs (hAMSCs) were established and characterized for cell surface markers of mesenchymal stem cell origin in conjunction with the potential for tri-lineage differentiation (adipogenic, chondrogenic, and osteogenic). Validated experimental hAMSCs were compared to commercially derived hBMSCs (Lonza) and hAMSCs (Invitrogen) for growth responsiveness and glioma tropism in response to glioma conditioned media obtained from primary glioma neurosphere cultures.ResultsCommercial and primary culture AMSCs and commercial BMSCs demonstrated no statistically significant difference in their migration towards glioma conditioned media in vitro. There was statistically significant difference in the proliferation rate of both commercial AMSCs and BMSCs as compared to primary culture AMSCs, suggesting primary cultures have a slower growth rate than commercially available cell lines.ConclusionsAdipose- and bone marrow-derived mesenchymal stem cells have similar in vitro glioma tropism. Given the well-documented ability to harvest larger numbers of AMSCs under local anesthesia, adipose tissue may provide a more efficient source of MSCs for research and clinical applications, while minimizing patient morbidity during cell harvesting.

Object Metastatic epidural spinal cord compression (MESCC) is a relatively common and debilitating complication of metastatic disease that often results in neurological deficits. Recent studies have supported decompressive surgery over radiation therapy for patients who present with MESCC. These studies, however, have grouped all patients with different histological types of metastatic disease into the same study population. The differential outcomes for patients with different histological types of metastatic disease therefore remain unknown. Methods An institutional database of patients undergoing decompressive surgery for MESCC at an academic tertiary-care institution between 1996 and 2006 was retrospectively reviewed. Patients with primary lung, breast, prostate, kidney, or gastrointestinal (GI) cancer or melanoma were identified. Fisher exact and log-rank analyses were used to compare pre-, peri-, and postoperative variables and survival for patients with these different types of primary cancers. Results Twenty-seven patients with primary lung cancer, 26 with breast cancer, 20 with prostate cancer, 21 with kidney cancer, 13 with GI cancer, and 7 with melanoma were identified and categorized. All of these patients were followed up for a mean ± SD of 10.8 ± 3.8 months following surgery. Patients with primary lung and prostate cancers were typically older than patients with other types of primary cancers. Patients with prostate cancer had the shortest duration of symptoms and more commonly presented with motor deficits, while patients with breast cancer more commonly had cervical spine involvement and compression fractures. For all histological types, > 90% of patients retained the ability to ambulate following surgery. However, the group with the highest percentage of patients who regained ambulatory function after decompressive surgery was the lung cancer group. Patients with breast or kidney cancer and those with melanoma had the highest median duration of survival following decompressive surgery. Conclusions The present study identifies differences in presenting symptoms, operative course, perioperative complications, long-term ambulatory outcomes, and duration of survival for patients with lung, breast, prostate, kidney, and GI cancers and melanoma. This understanding may allow better risk stratification for patients with MESCC.

This study provides reference charts detailing AFC frequency and AF SA as a function of age. Wide variability of AFC timing and AF size among healthy infants suggest that early or delayed AFC may represent normal variants.

Glioblastoma is the most common and aggressive type of primary brain tumor in adults. Average survival is approximately 1 year, but individual survival is heterogeneous. Using a single institutional experience, we have previously identified preoperative factors associated with survival and devised a prognostic scoring system based on these factors. The aims of the present study are to validate these preoperative factors and verify the efficacy of this scoring system using a multi-institutional cohort. Of the 334 patients in this study from three different institutions, the preoperative factors found to be negatively associated with survival in a Cox analysis were age >60 years (p < 0.0001), Karnofsky Performance Scale score ≤80 (p = 0.03), motor deficit (p = 0.02), language deficit (p = 0.04), and periventricular tumor location (p = 0.04). Patients possessing 0–1, 2, 3, and 4–5 of these variables were assigned a preoperative grade of 1, 2, 3, and 4, respectively. Patients with a preoperative grade of 1, 2, 3, and 4 had a median survival of 17.9, 12.3,10, and 7.5 months, respectively. Survival of each of these grades was statistically significant (p < 0.05) in log-rank analysis. This grading system, based only on preoperative variables, may provide patients and physicians with prognostic information that may guide medical and surgical therapy before any intervention is pursued.

Objective Peak incidence of glioblastoma multiforme (GBM) occurs in individuals aged 65 years and older. The goal was to evaluate the efficacy of carmustine wafers in prolonging survival for older GBM patients. Methods One hundred and thirty-three consecutive patients aged 65 years and older who underwent surgery for an intracranial primary (de novo) GBM from 1997–2007 were retrospectively reviewed. Among these 133 patients, 45 patients with carmustine wafer implantation were matched with 45 patients without implantation. These groups were matched for factors consistently shown to be associated with survival (age, Karnofsky performance scale, extent of resection, radiation therapy, and temozolomide). Survival was expressed as estimated Kaplan–Meier plots, and log-rank analysis was used to compare survival curves. Variables with P<0.05 were considered statistically significant. Results The mean (±standard deviation) age of the cohort was 73±5 years, and the median survival of the entire cohort was 5.9 months. Among patients with and without carmustine wafers, there were no significant differences in pre- and peri-operative variables. However, patients with carmustine wafers demonstrated prolonged survival as compared to patients without wafers. The median survival for patients with carmustine wafers was 8.7 months, while median survival for patients without wafers was 5.5 months (P=0.007). Likewise, in subgroup analysis, patients older than 70 years (P=0.0003) and 75 years (P=0.04) who had carmustine wafers had significantly longer survival than matched patients without wafers. Discussion Older patients with GBM may benefit from carmustine wafers. The survival for older patients who received carmustine wafers is significantly longer than matched patients who did not receive carmustine wafers.